This invention relates to topical formulations comprising heterocyclic compounds and their preparation and to their topical use in medicine in a mammal, including man, as anti-inflammatories.
Anti-inflammatory compounds may be assigned to one of two major groups of anti-inflammatory drugs according to their mode of action, namely aspirin-like drugs or corticosteroids. The major disadvantage of the aspirin-like drugs is that they exhibit unfavourable gastro-intestinal side-effects which have been attributed to their selective inhibition of the cyclo-oxygenase pathway of arachidonic acid metabolism (J. R. Vane, Inhibition of prostaglandin synthesis as a mechanism of action for the aspirin-like drugs, Nature (1971) 231, 232). The aspirin-like drugs give good symptomatic relief in chronic inflammation such as analgesia and reduced swelling. However the more chronic, leucocytemediated components of inflammation may proceed unchecked at the low doses administered to avoid the toxic side-effects. The corticosteroid anti-inflammatories do not inhibit oxygenation of arachidonic acid by inhibition of either the cyclo-oxygenase or lipoxygenase pathways in vitro although they have been shown to prevent prostaglandin synthesis in a number of different tissues. The major disadvantage of steroid-like anti-inflammatory drugs is their complicating systemic side-effects.
It is, therefore, an object of the present invention to provide anti-inflammatory formulations which do not exhibit the side-effects associated with these two groups of hitherto-known anti-inflammatory drugs.
U.S. Pat. No. 3,927,025 discloses formulations of compounds of formula (A) and salts thereof which are alleged to have anti-spasmodic activity. ##STR2## In (A), R is selected from alkyl, cycloalkyl, substituted cycloalkyl, aralkyl, substituted aralkyl, aryl and substituted aryl; R.sup.6 and R.sup.7 may each be selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl; and R.sup.3 is selected from hydrogen and the acyl radical of an organic carboxylic acid. Certain of the heterocyclic compounds embraced by formula (A) are known as chemical intermediates in U.S. Pat. No. 4,149,005, and U.K. patent specification Nos. 679678 and 679677. However, none of these patent specifications suggest that any of the compounds of formula (A) possess, or are likely to possess, anti-inflammatory, analgesic or anti-pyretic activity. This is not surprising since none of the antispasmodic agents described in The Pharmacological Basis of Therapeutics, 5th Edition, by Goodman and Gilman, pages 514 to 532 (Macmillian, (1975)) have anti-inflammatory activity and so it would not be expected for an antispasmodic agent to exhibit anti-inflammatory activity. Certain 1-alkyl-3-amino-5-arylpyrazol-2-ines are disclosed in U.K. patent specification No. 1 294 035 as having anti-inflammatory, analgesic or antipyretic activity.